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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-333124

ABSTRACT

Viral CD8 + epitopes are generated by the cellular turnover of viral proteins, predominantly by the proteasome. Mutations located within viral epitopes can result in escape from memory T cells but the contribution of mutations in flanking regions of epitopes in SARS-CoV-2 has not been investigated. Focusing on two of the most dominant SARS-CoV-2 nucleoprotein CD8 + epitopes, we identified mutations in epitope flanking regions and investigated the contribution of these mutations to antigen processing and T cell activation using SARS-CoV-2 nucleoprotein transduced B cell lines and in vitro proteasomal processing of peptides. We found that decreased NP 9-17 -B*27:05 CD8 + T cell responses to the NP-Q7K mutation correlated with lower epitope surface expression, likely due to a lack of efficient epitope production by the proteasome, suggesting immune escape caused by this mutation. In contrast, NP-P6L and NP-D103N/Y mutations flanking the NP 9-17 -B*27:05 and NP 105-113 -B*07:02 epitopes, respectively, increased CD8 + T cell responses associated with enhanced epitope production by the proteasome. Our results provide evidence that SARS-CoV-2 mutations outside the epitope could have a significant impact on antigen processing and presentation, thereby contributing to escape from immunodominant T cell responses. Alternatively, mutations could enhance antigen processing and efficacy of T cell recognition, opening new avenues for improving future vaccine designs. One Sentence Summary Natural mutations in the flanking regions of known immunodominant SARS-CoV-2 nucleoprotein epitopes can decrease CD8 + T cell responses leading to partial escape.

2.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-309642

ABSTRACT

NP 105-113 -B*07:02 specific CD8 + T-cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP 105-113 -B*07:02 specific T-cell clones and single cell sequencing were performed concurrently, with functional avidity and anti-viral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with TCR usage, transcriptome signature, and disease severity (acute N=77, convalescent N=52). We demonstrated a beneficial association of NP 105-113 -B*07:02 specific T-cells in COVID-19 disease progression, linked with expansion of T-cell precursors, high functional avidity and anti-viral effector function. Broad immune memory pools were narrowed post-infection but NP 105-113 -B*07:02 specific T-cells were maintained 6 months after infection with preserved anti-viral efficacy to the SARS-CoV-2 Victoria strain, as well as new Alpha, Beta and Gamma variants. Our data shows that NP 105-113 -B*07:02 specific T-cell responses associate with mild disease and high anti-viral efficacy, pointing to inclusion for future vaccine design.

3.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-328783

ABSTRACT

Little is known of the role of cytotoxic CD4 + T-cells in the control of viral replication. Here, we investigate CD4 + T-cell responses to three dominant SARS-CoV-2 epitopes and evaluate antiviral activity, including cytotoxicity and antiviral cytokine production. Diverse T cell receptor (TCR) usage including public TCRs were identified;surprisingly, cytotoxic CD4 + T-cells were found to have signalling and cytotoxic pathways distinct from classical CD8 + T-cells, with increased expression of chemokines and tissue homing receptors promoting migration. We show the presence of cytolytic CD4 + T-cells during primary infection associates with COVID-19 disease severity. Robust immune memory 6-9 months post-infection or vaccination provides CD4 + T-cells with potent antiviral activity. Our data support a model where CD4 + killer cells drive immunopathogenesis during primary infection and CD4 + memory responses are protective during secondary infection. Our study highlights the unique features of cytotoxic CD4 + T-cells that use distinct functional pathways, providing preventative and therapeutic opportunities.

4.
Nat Immunol ; 23(1): 50-61, 2022 01.
Article in English | MEDLINE | ID: covidwho-1545628

ABSTRACT

NP105-113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105-113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP105-113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP105-113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP105-113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design.


Subject(s)
HLA-B7 Antigen/immunology , Immunodominant Epitopes/immunology , Nucleocapsid Proteins/immunology , SARS-CoV-2/immunology , T-Lymphocytes, Cytotoxic/immunology , Aged , Amino Acid Sequence , Antibodies, Viral/immunology , Antibody Affinity/immunology , COVID-19/immunology , COVID-19/pathology , Cell Line, Transformed , Female , Gene Expression Profiling , Humans , Immunologic Memory/immunology , Male , Middle Aged , Receptors, Antigen, T-Cell/immunology , Severity of Illness Index , Vaccinia virus/genetics , Vaccinia virus/immunology , Vaccinia virus/metabolism
5.
iScience ; 24(11): 103353, 2021 Nov 19.
Article in English | MEDLINE | ID: covidwho-1509904

ABSTRACT

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.

6.
Nat Immunol ; 21(11): 1336-1345, 2020 11.
Article in English | MEDLINE | ID: covidwho-889210

ABSTRACT

The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4+ and/or CD8+ epitopes, including six immunodominant regions. Six optimized CD8+ epitopes were defined, with peptide-MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8+ T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design.


Subject(s)
Antigens, Viral/immunology , Betacoronavirus/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Immunologic Memory/immunology , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/prevention & control , Epitopes, T-Lymphocyte/immunology , Humans , Immunodominant Epitopes/immunology , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology , United Kingdom , Viral Vaccines/immunology
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